Supportive Care

Oxygen should be administered to patients with hypoxemia or shortness of breath. Emergency medical personnel should administer oxygen if the patient is dyspneic. Some prehospital providers can deliver aerosol treatments with beta-agonists, which may improve the patient's breathing. Patients with respiratory failure require endotracheal intubation and ventilator support.

Isotonic sodium chloride solution should be administered to patients who are in shock and have no component of heart failure.

Acute care may involve use of the following:

Oxygen, if the patient is dyspneic

Beta-agonists, if bronchospasm is present

Fluids, if dehydration is present

Acyclovir, if varicella or herpes pneumonia is suspected

Respiratory isolation

Antibiotics, if infiltrate is seen on the chest radiograph

Mechanical ventilation if respiratory failure is present or impending

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Influenza Pneumonia

Antiviral therapy is available for the treatment of influenza virus infection. The treatment of uncomplicated influenza is supportive in nature, consisting of rest and administration of antipyretics and analgesics. See Table 3 below.

Amantadine hydrochloride and rimantadine hydrochloride are approved for the prevention and treatment of influenza A virus infection. They are not active against influenza B virus infection. Both drugs are absorbed well orally, block the viral M2 protein ion channel, and inhibit the uncoating of the virus. Rimantadine is a synthetic analog of amantadine and has comparable therapeutic efficacy.

Treatment with these compounds has been associated with the emergence of viral resistance. The clinical significance of this is not known. Many of the current strains are not susceptible to amantadine/rimantadine (including H1N1 influenza virus), so empiric use of these agents as the only drug is not recommended.

These drugs trap the virus inside the infected respiratory epithelial cells and prevent spread to other cells. They are active against both influenza A and influenza B viruses. These newer drugs have a different safety profile and lower potential for inducing resistance, but they are much more expensive.

Peramivir (Rapivab) was approved by the FDA in December 2014 for use in adults as a single 600 mg IV dose. In clinical trials, a single intravenous dose of peramivir, a sialic acid analogue and a selective inhibitor of neuraminidases produced by influenza A and B viruses, is effective and well tolerated in subjects with uncomplicated seasonal influenza virus infection. At both 300 mg and 600 mg, peramivir significantly reduced the time to alleviation of symptoms in comparison with placebo.
[80] Additional data from over 2,700 subjects treated with peramivir in 27 clinical trials also supported its approval. It was available in the United States by emergency protocol during the 2009 H1N1 influenza pandemic.

The results of zanamivir studies have confirmed its efficacy only if therapy is started within 24-48 hours of symptom onset in febrile patients. Most studies have reported a similar window of opportunity for oseltamivir. Like the older agents, they reduce the course of influenza by approximately one day. Oseltamivir resistance emerged in the United States during the 2008-2009 influenza season.

For severe influenza pneumonia, antiviral medication should be given, even after the 48-hour window.

In a double-blind, randomized controlled trial, one inhalation of laninamivir octanoate was shown as effective for the treatment of seasonal influenza in adults. Effectiveness was also shown for the oseltamivir-resistant virus.
[81]

H1N1 influenza

In the 2009-2010 H1N1 influenza epidemic, the US Centers for Disease Control and Prevention (CDC) recommended oseltamivir or zanamivir for treatment of all hospitalized patients with suspected or confirmed cases and for outpatients at increased risk for complications of H1N1 infection.

As of September 2009, only 28 of 10,000 H1N1 isolates tested were resistant to oseltamivir (11 from the United States), and all were susceptible to zanamivir.

Although intravenous peramivir had not been formally FDA approved for the treatment of influenza during the 2009-2010 H1N1 pandemic, the FDA issued an emergency use authorization (EUA) for its use in hospitalized patients who had potentially life-threatening suspected or laboratory confirmed infection with H1N1. Under the EUA, treatment with IV peramivir was approved for patients who had not responded to either oral or inhaled antiviral therapy and/or drug delivery by a route other than IV that was not expected to be dependable or feasible.

Early administration of corticosteroids in patients with H1N1 who are admitted to the ICU has no apparent benefit.
[82]

Avian influenza

Avian H5N1 influenza should be treated with oseltamivir, even after the 48-hour window, because a reduction in mortality of hospitalized persons with seasonal influenza or avian influenza A (H5N1) virus infection was reported even when oseltamivir treatment was initiated later. The optimal duration and dose is not clear, but the WHO recommends consideration of higher dosage (eg, 150 mg PO bid) and longer duration in severe infections.

Avian H5N1 influenza has exhibited resistance to oseltamivir (clade 1 and subclade 2.1 with H274Y and N294S mutations). These resistant strains maintained susceptibility to zanamivir. Some viruses circulating in birds (subclade 2.3.4) demonstrated reduced susceptibility to zanamivir but sensitivity to the adamantanes (amantadine/rimantadine). Thus, for resistant strains (especially subclades 2.2 and 2.3.4), consideration for combination therapy with neuraminidase inhibitor-adamantane or oseltamivir-ribavirin, or even triple therapy with neuraminidase inhibitor-adamantane-ribavirin, should be given.
[56]

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Respiratory Syncytial Virus Pneumonia

As with influenza, treatment of uncomplicated respiratory syncytial virus (RSV) infection is supportive in nature.

Ribavirin, a nucleoside analog of guanosine, is the only effective antiviral agent currently available for the treatment of RSV pneumonia.
[1] Ribavirin acts by interfering with viral transcription. This drug is delivered as a small-particle aerosol. Data conflict regarding the efficacy of ribavirin therapy in RSV pneumonia. Overall, the preponderance of data suggests a benefit of ribavirin therapy in high-risk patients, such as hematopoietic stem cell transplant (HSCT) recipients.

Current recommendations are that ribavirin therapy should be considered only for severe illness and in high-risk patients for whom RSV infection is associated with high mortality, such as HSCT recipients.
[57] In these hosts, high-dose, short-duration aerosolized ribavirin (60 mg/mL for 2 h given by mask tid) has been used.

RSV-specific intravenous immunoglobulin, such as palivizumab (Synagis), which is a monoclonal antibody directed against the RSV fusion (F) glycoprotein, has also been used with aerosolized and oral ribavirin in high-risk patients, such as HSCT recipients, because this combination has been shown to increase survival in this group.
[52] Its use is endorsed in some guidelines, although not universally accepted or recommended.
[83, 84]

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Adenovirus Pneumonia

Cidofovir has demonstrated good in vitro activity against adenoviruses, including serotype 14. Cidofovir has shown some efficacy in treating adenovirus infection in immunocompromised patients, especially HSCT recipients.
[85] The dose is 5 mg/kg/wk for two weeks, then every two weeks plus probenecid 1.25 g/m2 given three hours before cidofovir and three and nine hours after each infusion. Alternate dosing is 1 mg/kg IV three times a week.

The in vitro activity of ribavirin against adenovirus, however, has been variable. For example, in one study, species C was susceptible to ribavirin, while other species were more variable.
[86] Some anecdotal reports exist regarding improvement in some patients with HSCT and leukemia, although other studies have not shown any efficacy. Thus, routine use of ribavirin is not recommended.
[87, 88, 89]

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Parainfluenza Virus Pneumonia

Treatment is mainly supportive in nature. Ribavirin has documented in vitro activity against parainfluenza virus (PIV), and aerosolized and oral ribavirin were associated with reduction in PIV shedding and clinical improvement in immunocompromised patients. Thus, in this latter, high-risk group, the use of ribavirin may be reasonable.
[90]

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Human Metapneumovirus Pneumonia

Although ribavirin has activity against human metapneumovirus (hMPV) similar to that which it has against RSV and although animal data have shown some promise, treatment data in humans are lacking, being confined to occasional case reports predominantly in the transplantation population.
[91, 92]

Immunoglobulin preparations (intravenous immunoglobulin [IVIG]) also seem to contain sufficient neutralizing titers, but this has not been extensively studied for use in hMPV pneumonia either—again with only isolated case reports in patients with transplantation, usually in combination with ribavirin.
[93]

Ribavirin is not active against SARS-CoV in vitro, and studies have not shown clinical efficacy. Therefore, this medication is not recommended for this infection.
[95]

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Varicella-Zoster Virus Pneumonia

Treatment of varicella pneumonia includes respiratory isolation until skin lesions heal, supportive care, administration of antiviral agents, and active and passive immunization. For treatment of documented varicella pneumonia in patients who are immunocompromised, acyclovir (10 mg/kg IV q8h for 7 d) has been shown to be effective.

For pregnant women in the third trimester, acyclovir at 10 mg/kg IV every eight hours for five days should be given, and consideration should be given for varicella-zoster immune globulin (VZIG) therapy.

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Measles Pneumonia

Treatment of measles pneumonia generally is supportive in nature. Children infected with HIV and adults who are immunosuppressed with measles pneumonia have been treated successfully with intravenous (20-35 mg/kg/d for 7 d) and aerosolized ribavirin, similar to the therapy for severe infections with RSV.
[96]

High-dose intravenous immunoglobulin (CMV immunoglobulin or IVIG) has been used successfully in conjunction with ganciclovir for the treatment of CMV pneumonia, decreasing the mortality rate to 0-47%. Combination therapy is based on the premise that lung injury is not solely due to direct damage by the virus but is a result of virally induced immunological reaction. In lung transplant recipients, ganciclovir with CMV immunoglobulin or IVIG has been associated with increased survival.
[98]

Foscarnet sodium, an inhibitor of viral DNA polymerase and reverse transcriptase, is an alternative drug for use in ganciclovir-resistant CMV pneumonia. The combination of foscarnet with ganciclovir may provide antiviral synergy, but it requires careful monitoring.
[99]

Cidofovir represents a third option, but scant data exist regarding its use in CMV pneumonia.

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Herpes Simplex Virus Pneumonia

Acyclovir inhibits viral DNA synthesis by competitively binding to viral DNA polymerase. Intravenous acyclovir (250 mg/m2 q8h) currently is the treatment of choice for herpes simplex virus (HSV) pneumonia. Because a significant proportion of patients may have concomitant bacterial pneumonia, empirical broad-spectrum antibiotic therapy that includes an antistaphylococcal drug should be instituted in patients with progressive HSV pneumonia who are unresponsive to antiviral therapy.

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Hantavirus Pneumonia

The treatment of hantavirus pulmonary syndrome (HPS) is supportive in nature and includes correction hypoxemia, lactic acidosis, and hypotension. Mechanical ventilation and optimal fluid management guided by hemodynamic monitoring are recommended, with avoidance of excessive administration of fluids and with use of cardiotonic drugs to counter the hemodynamic profile of decreased cardiac output and increased systemic vascular resistance. See the Cardiac Output calculator.

Although intravenous ribavirin has been associated with some success in the treatment of some Bunyaviridae viruses, such as Hantaan virus (hemorrhagic fever with renal syndrome), Rift Valley fever virus, and Crimean-Congo hemorrhagic fever virus, it has failed to show any efficacy in HPS, perhaps because death typically occurred within 24-48 hours of hospitalization.
[71]

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Prevention

Influenza

Annual fall vaccination of high-risk populations and healthcare workers is the most effective measure for decreasing morbidity and mortality from influenza.
[84] Each year's influenza vaccine contains the three virus strains (usually two type A strains and 1 type B strain) considered most likely to cause outbreaks based on epidemiologic surveillance.

The effectiveness of the vaccine depends on the age and general health status of the recipient and the antigenic similarity to the virus causing outbreaks that year. When the vaccine matches the prevalent influenza virus strain, the efficacy of the vaccine in healthy adults is reported to be in the range of 70-90%.

The effectiveness of widespread vaccination in elderly persons has been called into question. A recent meta-analysis of the efficacy, effectiveness, and safety of the influenza vaccine in patients older than 65 years found that vaccination is of benefit to residents of long-term care facilities but is of modest value in the community.
[101] However, the Centers for Disease Control and Prevention (CDC) still recommend immunization of all elderly patients.
[100, 102]

The CDC has recommended chemoprophylaxis in the following situations:

Close contacts of patients who are at high risk for complications of influenza.

Healthcare personnel, public health workers, and first responders who have had recognized and unprotected close contact exposure to a person with influenza during the person's infectious period (up to 7 d after onset of illness).

Chemoprophylaxis should be considered when outbreaks occur in nursing homes. Everyone in the institution, including the unvaccinated staff and other coworkers, should receive prophylactic therapy for at least two weeks during the outbreak.

The CDC issues updated interim guidance on antiviral treatment and prophylaxis of seasonal influenza, based on resistance patterns of the circulating viral strains.

Local influenza surveillance data and laboratory testing can also assist the physician regarding the antiviral agent choice.

Vaccines for avian H5N1 influenza are currently being developed and studied, and vaccinations have been performed in avian livestock (via whole-virus inactivated vaccine, recombinant fowlpox vaccine, and recombinant Newcastle disease vaccine.)

An alternative to RSV immunoglobulin is palivizumab (Synagis), which is an intramuscularly administered humanized monoclonal antibody preparation. Prophylaxis with this agent results in a 55% reduction in hospitalization secondary to RSV infection in high-risk pediatric patients.

Vaccines are under development, including subunit vaccines directed against two major surface glycoproteins (F, G proteins), a polypeptide vaccine (BBG2Na), and live-attenuated vaccines, the latter of which have been promising in adults.

Adenovirus

An oral live vaccine was available against serotypes 4 and 7, taking advantage of the fact that exposure of these strains to the gastrointestinal tract does not result in illness. This vaccine was used primarily in military recruit populations, with excellent results, but it has not been available since 1999. Recrudescence of adenovirus type 3, 4, and 7 has occurred in the military.

Other live and inactivated virus vaccines have been hampered by their oncogenicity in animal models. Vaccines against the capsid (and free of DNA) are currently being studied.

Parainfluenza virus

No vaccine is available, but live, attenuated, intranasally administered parainfluenza type 3 vaccines were under development.

Human metapneumovirus

No vaccine is available, although a live-attenuated bovine parainfluenza virus type 3 vaccine with human metapneumovirus F gene was being studied.
[103]

Varicella-zoster virus

A live attenuated varicella vaccine is recommended for patients who did not have varicella infection by age 13 years and for anyone who is susceptible to varicella-zoster virus (VZV) (VZV antibody negative). The vaccine should not be given to pregnant women. Children are now routinely immunized before age 12-18 months.

Intramuscular administration of varicella-zoster immunoglobulin (125 U/10 kg to 625 units maximum) is indicated as passive immunization of VZV-seronegative personnel at risk for complications within 96 hours of being exposed to VZV (eg, immunosuppressed hosts, such as those with HIV or with malignancies; those on long-term steroid therapy; pregnant patients, and neonates whose mothers acquire VZV within five days before, to 48 hours after, delivery).

Measles

The measles vaccine is a live attenuated virus vaccine (part of measles-mumps-rubella [MMR] vaccine) and should be given to everyone except pregnant women or persons who are severely immunocompromised. HIV-infected persons who are asymptomatic or only mildly symptomatic should be vaccinated.

Postexposure prophylaxis of patients who are immunocompromised with intravenous immune globulin is effective if administered within 6 days of exposure to infectious cases of measles.

Cytomegalovirus

Cytomegalovirus (CMV) infection is prevented in transplant patients by attempts to match the CMV seropositivity between the donor and the recipient and by careful administration of CMV-negative transfusions of blood and blood products.

Hematopoietic stem cell transplant (HSCT) recipients who are CMV-negative are given prophylactic ganciclovir before and after transplantation. Solid organ transplant (SOT) recipients who are CMV-negative and receiving their organ from CMV-positive donors typically receive ganciclovir for three months post transplantation.

Herpes simplex virus

Chemoprophylaxis of high-risk seropositive patients during induction of immunosuppression for transplantation is recommended.

Acyclovir is routinely prescribed at maintenance doses for the first month after transplantation.

Hantavirus

No vaccine is available or in development. The only means of deterrence is by avoiding rodent contact and/or inhalation/aerosolization of areas of possible rodent excreta. If contact is unavoidable (ie, need to sweep dirty areas where rodents live), use of a respiratory mask is prudent.

Hematopoietic cell transplantation recipients

An international committee has produced guidelines for preventing infectious complications among HCT recipients. These guidelines include recommendations on use of antivirals for prevention or preemptive treatment of specific infections, as well as recommendations on vaccines.
[104]

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Consultations

Patients suspected of having viral pneumonia may benefit from consultation with pulmonary and infectious diseases specialists.

Centers for Disease Control and Prevention. Updated CDC Estimates of 2009 H1N1 Influenza Cases, Hospitalizations and Deaths in the United States, April 2009 - April 10, 2010. Available at http://www.cdc.gov/h1n1flu/estimates_2009_h1n1.htm. Accessed: August 8, 2014.

Centers for Disease Control and Prevention. Seasonal Influenza (Flu). Recommendations of the Advisory Committee on Immunization Practices (ACIP). Available at http://www.cdc.gov/flu/professionals/acip/. Accessed: August 8, 2014.

Pneumonia, viral: A 52-year-old woman developed fever, cough, and dyspnea. She also developed a rash that was prominent over the face and the trunk. The chest radiograph showed interstitial infiltrates, with suggestion of a micronodular process. The Tzanck smear results from the skin vesicle suggest varicella-zoster virus.

Pneumonia, viral: A 52-year-old woman developed fever, cough, and dyspnea. She also developed a rash that was prominent over the face and the trunk. The chest radiograph showed interstitial infiltrates, with suggestion of a micronodular process. The Tzanck smear results from the skin vesicle suggest varicella-zoster virus. She was treated with acyclovir; resolution of varicella-zoster virus infection occurred after 7 days of therapy.

Bilateral interstitial infiltrates in a 31-year-old patient with influenza pneumonia.

Right-middle-lobe infiltrate in a 2-month-old boy with pneumonia due to respiratory syncytial virus (RSV).

High-power Papanicolaou (Pap) stain showing a virus on a bronchial wash. Viruses in general show "smudgy" nuclei, may or may not show nuclear or cytoplasmic inclusions, and may demonstrate other features such as multinucleation or margination of chromatin to the periphery of the cell nucleus. Certain features are more indicative of one virus over another. This is an example of herpes virus (cells infected are located in the center right).

High-power Papanicolaou (Pap) stain of cytomegalovirus (center). This cell has a very large, dark intranuclear inclusion.

High-power hematoxin-and-eosin stained herpes simplexvirus, characterized by "smudgy" degenerating nuclei. Some cells are multinucleated with margination of the chromatin to the periphery of the nuclei and molding of the nuclei to each other.

Gloria J Kuhn, DO, PhD, FACEP Professor, Vice-Chair of Academic Affairs, Dept of Emergency Medicine, Wayne State University School of Medicine; Professor, Department of Internal Medicine, Section of Emergency Medicine, Michigan State University College of Osteopathic Medicine

Satinder P Singh, MD, FCCP Professor of Radiology and Medicine, Chief of Cardiopulmonary Radiology, Director of Cardiac CT, Director of Combined Cardiopulmonary and Abdominal Radiology, Department of Radiology, University of Alabama at Birmingham School of Medicine